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6 Publications

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    09/16/11 | Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop.
    Yang Y, Atasoy D, Su HH, Sternson SM
    Cell. 2011 Sep 16;146:992-1003. doi: 10.1016/j.cell.2011.07.039

    Synaptic plasticity in response to changes in physiologic state is coordinated by hormonal signals across multiple neuronal cell types. Here, we combine cell-type-specific electrophysiological, pharmacological, and optogenetic techniques to dissect neural circuits and molecular pathways controlling synaptic plasticity onto AGRP neurons, a population that regulates feeding. We find that food deprivation elevates excitatory synaptic input, which is mediated by a presynaptic positive feedback loop involving AMP-activated protein kinase. Potentiation of glutamate release was triggered by the orexigenic hormone ghrelin and exhibited hysteresis, persisting for hours after ghrelin removal. Persistent activity was reversed by the anorexigenic hormone leptin, and optogenetic photostimulation demonstrated involvement of opioid release from POMC neurons. Based on these experiments, we propose a memory storage device for physiological state constructed from bistable synapses that are flipped between two sustained activity states by transient exposure to hormones signaling energy levels.

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    09/08/11 | Metabolism: let them eat fat.
    Sternson SM
    Nature. 2011 Sep 8;477(7363):166-7. doi: 10.1038/477166a

    A specialist neuron uses an intriguing process to help control the body's response to hunger. A lipid pathway involving the breakdown of cellular components regulates the expression of a neuropeptide that affects feeding and body weight.

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    09/02/11 | Chemical and genetic engineering of selective ion channel-ligand interactions.
    Magnus CJ, Lee PH, Atasoy D, Su HH, Looger LL, Sternson SM
    Science. 2011 Sep 2;333(6047):1292-6. doi: 10.1126/science.1206606

    Ionic flux mediates essential physiological and behavioral functions in defined cell populations. Cell type-specific activators of diverse ionic conductances are needed for probing these effects. We combined chemistry and protein engineering to enable the systematic creation of a toolbox of ligand-gated ion channels (LGICs) with orthogonal pharmacologic selectivity and divergent functional properties. The LGICs and their small-molecule effectors were able to activate a range of ionic conductances in genetically specified cell types. LGICs constructed for neuronal perturbation could be used to selectively manipulate neuron activity in mammalian brains in vivo. The diversity of ion channel tools accessible from this approach will be useful for examining the relationship between neuronal activity and animal behavior, as well as for cell biological and physiological applications requiring chemical control of ion conductance.

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    07/01/11 | Flip-flop memory circuit uses a synaptic AMPK-dependent positive feedback loop and is switched by hunger state.
    Y.Yang , D.Atasoy , S.Sternson
    Appetite. 2011 Jul 01;57(1):47. doi: 10.1016/j.appet.2011.05.296

    Synaptic plasticity in response to changes in physiologic state is coordinated by hormonal signals across multiple neuronal cell types, but the significance and underlying mechanisms are unclear. Here, we combine cell type-specific electrophysiological, pharmacological, and optogenetic techniques to dissect neural circuits and molecular pathways controlling synaptic plasticity onto AGRP neurons, a population that regulates feeding. We find that food deprivation elevates excitatory synaptic input, which is mediated by a presynaptic positive feedback loop involving AMP-activated protein kinase. Potentiation of glutamate release was triggered by the orexigenic hormone ghrelin and exhibited hysteresis, persisting for hours after ghrelin removal. Persistent activity was reversed by the anorexigenic hormone leptin, and optogenetic photostimulation demonstrated involvement of opioid release from POMC neurons. Based on these experiments, we propose a memory storage device for physiological state constructed from bistable synapses that are flipped between two sustained activity states by transient exposure to hormones signaling energy levels. Supported by: Howard Hughes Medical Institute.

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    03/01/11 | AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training.
    Aponte Y, Atasoy D, Sternson SM
    Nature Neuroscience. 2011 Mar;14(3):351-5. doi: 10.1038/nn.2739

    Two intermingled hypothalamic neuron populations specified by expression of agouti-related peptide (AGRP) or pro-opiomelanocortin (POMC) positively and negatively influence feeding behavior, respectively, possibly by reciprocally regulating downstream melanocortin receptors. However, the sufficiency of these neurons to control behavior and the relationship of their activity to the magnitude and dynamics of feeding are unknown. To measure this, we used channelrhodopsin-2 for cell type-specific photostimulation. Activation of only 800 AGRP neurons in mice evoked voracious feeding within minutes. The behavioral response increased with photoexcitable neuron number, photostimulation frequency and stimulus duration. Conversely, POMC neuron stimulation reduced food intake and body weight, which required melanocortin receptor signaling. However, AGRP neuron-mediated feeding was not dependent on suppressing this melanocortin pathway, indicating that AGRP neurons directly engage feeding circuits. Furthermore, feeding was evoked selectively over drinking without training or prior photostimulus exposure, which suggests that AGRP neurons serve a dedicated role coordinating this complex behavior.

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    02/14/11 | Adeno-associated viral vectors for mapping, monitoring, and manipulating neural circuits.
    Sternson S, Betley JN
    Human Gene Therapy. 2011 Feb 14;22(6):669-77. doi: 10.1089/hum.2010.204

    Understanding the structure and function of neural circuits are central questions in neuroscience research. To address these questions, new genetically encoded tools have been developed for mapping, monitoring, and manipulating neurons. Essential to implementation of these tools is their selective delivery to defined neuronal populations in the brain. This has been facilitated by recent improvements in cell type-specific transgene expression using recombinant adeno-associated viral vectors. Here, we highlight these developments and discuss areas for improvement that could further expand capabilities for neural circuit analysis.

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